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| | <StructureSection load='5cep' size='340' side='right'caption='[[5cep]], [[Resolution|resolution]] 1.99Å' scene=''> | | <StructureSection load='5cep' size='340' side='right'caption='[[5cep]], [[Resolution|resolution]] 1.99Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5cep]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CEP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5cep]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CEP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=50E:N-(5-PIPERIDIN-4-YL-1-PROPAN-2-YL-PYRAZOL-3-YL)-4-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE'>50E</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cen|5cen]], [[5ceo|5ceo]], [[5ceq|5ceq]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=50E:N-(5-PIPERIDIN-4-YL-1-PROPAN-2-YL-PYRAZOL-3-YL)-4-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE'>50E</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP3K12, ZPK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cep OCA], [https://pdbe.org/5cep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cep RCSB], [https://www.ebi.ac.uk/pdbsum/5cep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cep ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cep OCA], [http://pdbe.org/5cep PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cep RCSB], [http://www.ebi.ac.uk/pdbsum/5cep PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cep ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/M3K12_HUMAN M3K12_HUMAN]] May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. | + | [https://www.uniprot.org/uniprot/M3K12_HUMAN M3K12_HUMAN] May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.
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| - | Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12).,Patel S, Harris SF, Gibbons P, Deshmukh G, Gustafson A, Kellar T, Lin H, Liu X, Liu Y, Liu Y, Ma C, Scearce-Levie K, Ghosh AS, Shin YG, Solanoy H, Wang J, Wang B, Yin J, Siu M, Lewcock JW J Med Chem. 2015 Oct 2. PMID:26431428<ref>PMID:26431428</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5cep" style="background-color:#fffaf0;"></div>
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| - | == References ==
| + | |
| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Mitogen-activated protein kinase kinase kinase]]
| + | [[Category: HARRIS SF]] |
| - | [[Category: HARRIS, S F]] | + | [[Category: YIN J]] |
| - | [[Category: YIN, J]] | + | |
| - | [[Category: Kinase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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